Prevention of Premature Ovulation by Administration of Gonadotropin Releasing Hormone Antagonist the day After Ovulation Triggering in Diminished Ovarian Reserve Patients

Abstract

Objective The aim of the present retrospective study was to investigate the effectiveness of single-dose gonadotropin releasing hormone (GnRH) antagonist administration, the day after human chorionic gonadotropin (hCG) triggering for final oocyte maturation, on the prevention of premature luteinization in patients with diminished ovarian reserve in in-vitro fertilization (IVF) cycles. The secondary objective of the study was to search the effect of this protocol on pregnancy outcomes.

Methods This is a retrospective study including 267 infertile patients who have single antral follicle seen with ultrasonography on the 2^nd or 3^rd day of the menstrual cycle before starting IVF treatment. We randomized patients into two groups. The case group comprised patients who had single-dose GnRH antagonist injection the day after hCG triggering formed, and the patients who had the standard treatment regime formed the control group. In both groups, the oocytes were collected 36 hours after hCG injection.

Results The premature ovulation rate was significantly low in the case group compared with the control group (6.86 versus 20.6% per scheduled cycle) (p = 0.022). Also, the oocyte retrieval rate (93.14 versus 67.87% per scheduled cycle) (p = 0.013), the oocyte maturity rate (79.42 versus 47.87%) (p = 0.041), the fertilization rate (65.68 versus 34.54%) (p = 0.018), and the embryo transfer rate per scheduled cycle (44.11 versus 18.78%) (p = 0.003) were higher in the GnRH antagonist group than in the control group.

Conclusion The administration of GnRH antagonist the day after hCG trigger in IVF treatments of patients with diminished ovarian reserve enabled a significant decrease in the rate of premature ovulation but had no effect on live birth rate.

Resumo

Objetivo O objetivo do presente estudo retrospectivo foi investigar a eficácia da administração do antagonista do hormônio liberador da gonadotrofina (GnRH) em dose única no dia seguinte ao desencadeamento da gonadotrofina coriônica humana (hCG) para a maturação final do oócito, na prevenção da luteinização prematura em pacientes com diminuição do ovário reserva em ciclos de fertilização in vitro (FIV). O objetivo secundário do estudo foi pesquisar o efeito deste protocolo nos resultados da gravidez.

Métodos Trata-se de um estudo retrospectivo incluindo 267 pacientes inférteis que apresentam um único folículo antral visto por ultrassonografia no 2° ou 3° dia do ciclo menstrual antes de iniciar o tratamento de FIV. Nós randomizamos os pacientes em dois grupos. Os pacientes que receberam injeção de antagonista de GnRH em dose única no dia seguinte ao desencadeamento do hCG formaram o grupo caso, e os pacientes que receberam o regime de tratamento padrão formaram o grupo controle. Em ambos os grupos, os oócitos foram coletados 36 horas após a injeção de hCG.

Resultados A taxa de ovulação prematura foi significativamente baixa no grupo caso em comparação com o grupo controle (6,86 versus 20,6% por ciclo programado) (p = 0,022). Além disso, a taxa de recuperação de oócitos (93,14 versus 67,87% por ciclo programado) (p = 0,013), a taxa de maturidade do oócito (79,42 versus 47,87%) (p = 0,041), a taxa de fertilização (65,68 versus 34,54%) (p = 0,018) e a taxa de transferência de embriões por ciclo programado (44,11 versus 18,78%) (p = 0,003) foram maiores no grupo antagonista de GnRH do que no grupo controle.

Conclusão A administração de antagonista de GnRH, no dia seguinte ao desencadeamento de hCG em tratamentos de FIV de pacientes com reserva ovariana diminuída permitiu uma redução significativa na taxa de ovulação precoce, mas não teve efeito na taxa de nascidos vivos.

Keywords

diminished ovarian reserve - GnRH antagonist - M₂ oocyte - premature ovulation - pregnancy rates

Palavras-chave

reserva ovariana diminuída - antagonista de GnRH - oócito M2 - ovulação prematura - taxas de gravidez

Contributions

All authors participated in the concept and design of the present study; in the analysis and interpretation of data; in the draft or revision of the manuscript; and they have approved the manuscript as submitted. All authors are responsible for the reported research.

Publication History

Received: 21 February 2021

Accepted: 09 August 2021

Article published online:
09 February 2022

• References

• 1 Vaiarelli A, Cimadomo D, Ubaldi N, Rienzi L, Ubaldi FM. What is new in the management of poor ovarian response in IVF?. Curr Opin Obstet Gynecol 2018; 30 (03) 155-162
• 2 Pelinck MJ, Hoek A, Simons AH, Heineman MJ. Efficacy of natural cycle IVF: a review of the literature. Hum Reprod Update 2002; 8 (02) 129-139
• 3 Fluker M, Grifo J, Leader A, Levy M, Meldrum D, Muasher SJ. et al; North American Ganirelix Study Group. Efficacy and safety of ganirelix acetate versus leuprolide acetate in women undergoing controlled ovarian hyperstimulation. Fertil Steril 2001; 75 (01) 38-45
• 4 Al-Inany HG, Youssef MA, Ayeleke RO, Brown J, Lam WS, Broekmans FJ. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology. Cochrane Database Syst Rev 2016; 4-25
• 5 Borm G, Mannaerts B. Treatment with the gonadotrophin-releasing hormone antagonist ganirelix in women undergoing ovarian stimulation with recombinant follicle stimulating hormone is effective, safe and convenient: results of a controlled, randomized, multicentre trial. The European Orgalutran Study Group. Hum Reprod 2000; 15 (07) 1490-1498
• 6 Schoolcraft WB, Surrey ES, Minjarez DA, Stevens JM, Gardner DK. Management of poor responders: can outcomes be improved with a novel gonadotropin-releasing hormone antagonist/letrozole protocol?. Fertil Steril 2008; 89 (01) 151-156
• 7 Reichman DE, Zakarin L, Chao K, Meyer L, Davis OK, Rosenwaks Z. Diminished ovarian reserve is the predominant risk factor for gonadotropin-releasing hormone antagonist failure resulting in breakthrough luteinizing hormone surges in in vitro fertilization cycles. Fertil Steril 2014; 102 (01) 99-102
• 8 Messinis IE, Vanakara P, Zavos A, Verikouki C, Georgoulias P, Dafopoulos K. Failure of the GnRH antagonist ganirelix to block the positive feedback effect of exogenous estrogen in normal women. Fertil Steril 2010; 94 (04) 1554-1556
• 9 Balasch J, Miró F, Burzaco I, Casamitjana R, Civico S, Ballescá JL. et al. The role of luteinizing hormone in human follicle development and oocyte fertility: evidence from in-vitro fertilization in a woman with long-standing hypogonadotrophic hypogonadism and using recombinant human follicle stimulating hormone. Hum Reprod 1995; 10 (07) 1678-1683
• 10 Thelmo MC, Acacio BD, Nouriani M. Peak serum estradiol (E2) is a predictor of pregnancy outcome in vitro fertilization (IVF). Fertil Steril (Poster Presentation Assisted Reproductive Technology) 2006; 86 :(3, Suppl): 187
• 11 Hattori K, Orisaka M, Fukuda S, Tajima K, Yamazaki Y, Mitzutani T. et al. Luteinizing hormone facilitates antral follicular maturation and survival via thecal paracrine signaling in cattle. Endocrinology 2018; 159 (06) 2337-2347
• 12 Gizzo S, Andrisani A, Noventa M, Manfè S, Oliva A, Gangemi M. et al. Recombinant LH supplementation during IVF cycles with a GnRH-antagonist in estimated poor responders: A cross-matched pilot investigation of the optimal daily dose and timing. Mol Med Rep 2015; 12 (03) 4219-4229
• 13 Wong PC, Qiao J, Ho C, Ramaraju GA, Wiweko B, Takehara Y. et al; Asia Pacific Fertility Advisory Group. Current opinion on use of luteinizing hormone supplementation in assisted reproduction therapy: an Asian perspective. Reprod Biomed Online 2011; 23 (01) 81-90
• 14 Raju GA, Chavan R, Deenadayal M, Gunasheela D, Gutgutia R, Haripriya G. et al. Luteinizing hormone and follicle stimulating hormone synergy: A review of role in controlled ovarian hyper-stimulation. J Hum Reprod Sci 2013; 6 (04) 227-234
• 15 Ferrero S, Abbamonte LH, Privamera MR, Levi S, Venturini PL, Anserini P. Flexible GnRH antagonist protocol versus GnRH agonist long protocol in patients at high risk of ovarian hyperstimulation syndrome: a prospective randomized controlled trial. Fertil Steril 2010; 94 (4, Suppl) S28
• 16 Depalo R, Trerotoli P, Chincoli A, Vacca MP, Lamanna G, Cicinelli E. Endogenous luteinizing hormone concentration and IVF outcome during ovarian stimulation in fixed versus flexible GnRH antagonist protocols: An RCT. Int J Reprod Biomed 2018; 16 (03) 175-182
• 17 Tarlatzis BC, Zepiridis L, Grimbizis G, Bontis J. Clinical management of low ovarian response to stimulation for IVF: a systematic review. Hum Reprod Update 2003; 9 (01) 61-76
• 18 El-Toukhy T, Khalaf Y, Hart R, Taylor A, Braude P. Young age does not protect against the adverse effects of reduced ovarian reserve–an eight year study. Hum Reprod 2002; 17 (06) 1519-1524
• 19 Polyzos NP, Nwoye M, Corona R, Blockeel C, Stoop D, Haentjens P. et al. Live birth rates in Bologna poor responders treated with ovarian stimulation for IVF/ICSI. Reprod Biomed Online 2014; 28 (04) 469-474
• 20 Kolibianakis E, Zikopoulos K, Camus M, Tournaye H, Van Steirteghem A, Devroey P. Modified natural cycle for IVF does not offer a realistic chance of parenthood in poor responders with high day 3 FSH levels, as a last resort prior to oocyte donation. Hum Reprod 2004; 19 (11) 2545-2549